The PRKCI and SOX2 Oncogenes Are Coamplified and Cooperate to Activate Hedgehog Signaling in Lung Squamous Cell Carcinoma

Justilien, Verline; Walsh, Michael P.; Ali, Syed Azmal; Thompson, E. Aubrey; Murray, Nicole R.; Fields, Alan P.

doi:10.1016/j.ccr.2014.01.008

Cited by 270 publications

(303 citation statements)

References 67 publications

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“…Justilien et al first reported a mechanism by which PRKCI forms a complex with ECT2-PAR6A to drive transformed growth through activation of a RAC1-PAK-MEK1-ERK1,2 signaling axis in NSCLC (14,25). Recently, the same group reported a functional link of PRKCI and SOX2 to activate hedgehog signaling in lung SCC (30 We also demonstrate that although genomic amplification is a key mechanism of FXR1 gene overexpression, it is the gene expression level that drives tumor progression in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 94%

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

Qian

Hassanein

Hoeksema

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies.

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Section: Discussionmentioning

confidence: 94%

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

Qian

Hassanein

Hoeksema

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Although criteria for their characterization have been proposed [37], particularly for amplified genes, they stipulate multiple lines of independent evidence which require considerable resources and, as such, have not been generated for most loci. Moreover, it is possible that in some instances where a minimal region of amplification contains more than one gene, such as the 11q13/14 locus which defines IntClust 2, that adjacent genes may act in a concerted manner to confer a selective growth advantage just as has been observed in lung cancer [38]. The conception of IntClust was pragmatic in attempting to minimize the influence of passenger genes.…”

Section: Deletionsmentioning

confidence: 99%

Genome-driven integrated classification of breast cancer validated in over 7,500 samples

et al. 2014

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Background: IntClust is a classification of breast cancer comprising 10 subtypes based on molecular drivers identified through the integration of genomic and transcriptomic data from 1,000 breast tumors and validated in a further 1,000. We present a reliable method for subtyping breast tumors into the IntClust subtypes based on gene expression and demonstrate the clinical and biological validity of the IntClust classification. Results: We developed a gene expression-based approach for classifying breast tumors into the ten IntClust subtypes by using the ensemble profile of the index discovery dataset. We evaluate this approach in 983 independent samples for which the combined copy-number and gene expression IntClust classification was available. Only 24 samples are discordantly classified. Next, we compile a consolidated external dataset composed of a further 7,544 breast tumors. We use our approach to classify all samples into the IntClust subtypes. All ten subtypes are observable in most studies at comparable frequencies. The IntClust subtypes are significantly associated with relapse-free survival and recapitulate patterns of survival observed previously. In studies of neo-adjuvant chemotherapy, IntClust reveals distinct patterns of chemosensitivity. Finally, patterns of expression of genomic drivers reported by TCGA (The Cancer Genome Atlas) are better explained by IntClust as compared to the PAM50 classifier.

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“…18,25 Shh signaling involves carcinogenesis, drug resistance, and poor prognosis of various types of cancers. [26][27][28] In this study, we determined that IR might activate Shh signaling to protect cancer cells. Accordingly, synthetic Shh peptides protected human glioblastoma cells from IR-mediated death.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Sonic hedgehog signaling and WW domain containing oxidoreductase WOX1 expression enhances radiosensitivity of human glioblastoma cells

Chiang

Chen

Chi

et al. 2015

Exp Biol Med (Maywood)

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WW domain containing oxidoreductase, designated WWOX, FOR or WOX1, is a known pro-apoptotic factor when ectopically expressed in various types of cancer cells, including glioblastoma multiforme (GBM). The activation of sonic hedgehog (Shh) signaling, especially paracrine Shh secretion in response to radiation, is associated with impairing the effective irradiation of cancer cells. Here, we examined the role of Shh signaling and WOX1 overexpression in the radiosensitivity of human GBM cells. Our results showed that ionizing irradiation (IR) increased the cytoplasmic Shh and nuclear Gli-1 content in GBM U373MG and U87MG cells. GBM cells with exogenous Shh treatment exhibited similar results. Pretreatment with Shh peptides protected U373MG and U87MG cells against IR in a dose-dependent manner. Cyclopamine, a Hedgehog/Smoothened (SMO) inhibitor, reversed the protective effect of Shh in U87MG cells. Cyclopamine increased Shh plus IR-induced H2AX, a marker of DNA doublestrand breaks, in these cells. To verify the role of Shh signaling in the radiosensitivity of GBM cells, we tested the effect of the Gli family zinc finger 1 (Gli-1) inhibitor zerumbone and found that it could sensitize GBM cells to IR. We next examined the role of WOX1 in radiosensitivity. Overexpression of WOX1 enhanced the radiosensitivity of U87MG (possessing wild type p53 or WTp53) but not U373MG (harboring mutant p53 or MTp53) cells. Pretreatment with Shh peptides protected both WOX1-overexpressed U373MG and U87MG cells against IR and increased the cytoplasmic Shh and nuclear Gli-1 content. Zerumbone enhanced the radiosensitivity of WOX1-overexpressed U373MG and U87MG cells. In conclusion, overexpression of WOX1 preferentially sensitized human GBM cells possessing wild type p53 to radiation therapy. Blocking of Shh signaling may enhance radiosensitivity independently of the expression of p53 and WOX1. The crosstalk between Shh signaling and WOX1 expression in human glioblastoma warrants further investigation.

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The PRKCI and SOX2 Oncogenes Are Coamplified and Cooperate to Activate Hedgehog Signaling in Lung Squamous Cell Carcinoma

Cited by 270 publications

References 67 publications

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

Genome-driven integrated classification of breast cancer validated in over 7,500 samples

Modulation of Sonic hedgehog signaling and WW domain containing oxidoreductase WOX1 expression enhances radiosensitivity of human glioblastoma cells

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